ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer models.
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ABSTRACT:
SUBMITTER: Polonio-Alcala E
PROVIDER: S-EPMC9198345 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer models.
Polonio-Alcalá Emma E Solé-Sánchez Sònia S Muñoz-Guardiola Pau P Megías-Roda Elisabet E Perez-Montoyo Héctor H Yeste-Velasco Marc M Alfón Jose J Lizcano Jose Miguel JM Domènech Carles C Ruiz-Martínez Santiago S Puig Teresa T
Cancer communications (London, England) 20220316 6
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Project description:BackgroundDysregulated energy metabolism has emerged as a defining hallmark of cancer, particularly evident in triple-negative breast cancer (TNBC). Distinct from other breast cancer subtypes, TNBC exhibits heightened glycolysis and aggressiveness. However, the transcriptional mechanisms of aerobic glycolysis in TNBC remains poorly understood.MethodsThe Cancer Genome Atlas (TCGA) cohort was utilized to identify genes associated with glycolysis. The role of FOSL1 in glycolysis and tumor growth in TNBC cells was confirmed through both loss-of-function and gain-of-function experiments. The subcutaneous xenograft model was established to evaluate the therapeutic potential of targeting FOSL1 in TNBC. Additionally, chromatin immunoprecipitation and luciferase reporter assays were employed to investigate the transcriptional regulation of glycolytic genes mediated by FOSL1.ResultsFOSL1 is identified as a pivotal glycolysis-related transcription factor in TNBC. Functional verification shows that FOSL1 enhances the glycolytic metabolism of TNBC cells, as evidenced by glucose uptake, lactate production, and extracellular acidification rates. Notably, FOSL1 promotes tumor growth in TNBC in a glycolysis-dependent manner, as inhibiting glycolysis with 2-Deoxy-D-glucose markedly diminishes the oncogenic effects of FOSL1 in TNBC. Mechanistically, FOSL1 transcriptionally activates the expression of genes such as SLC2A1, ENO1, and LDHA, which further accelerate the glycolytic flux. Moreover, FOSL1 is highly expressed in doxorubicin (DOX)-resistant TNBC cells and clinical samples from cases of progressive disease following neoadjuvant chemotherapy. Targeting FOSL1 proves effective in overcoming chemoresistance in DOX-resistant MDA-MB-231 cells.ConclusionIn summary, FOSL1 establishes a robust link between aerobic glycolysis and carcinogenesis, positioning it as a promising therapeutic target, especially in the context of TNBC chemotherapy.
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Project description:BackgroundApatinib is a new generation of small molecule tyrosine kinase inhibitor, which can highly selectively inhibit phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2). This study aimed to investigate the synergistic effects of apatinib and paclitaxel (PTX) on triple-negative breast cancer (TNBC) in vivo and in vitro, and to explore the molecular mechanism of the PI3K/p65/Bcl-xl pathway.MethodsIn vitro, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) method, flow cytometry (FCM), wound healing assay, and transwell matrix assay were conducted to measure the effects of apatinib and PTX on cell viability, apoptosis, migration, and invasion in TNBC cell line MDA-MB-468. Western blot (WB) was conducted to detect protein expression levels of PI3K, p65, and Bcl-xl after the application of apatinib and PTX. In vivo, MDA-MB-468 tumor-bearing nude mice were treated with apatinib and PTX, and tumor growth was observed.ResultsIn vitro, apatinib and PTX could synergistically suppress the cell viability, the combined group had the most obvious effect. Apatinib and PTX could promote apoptosis and suppress migration and invasion of TNBC cells. Apatinib could reduce the expression of p-PI3K, p65, and Bcl-xl proteins (P<0.05). In vivo, apatinib and PTX could inhibit tumor size and weight of model mice, and the combined agents had a more significant effect.ConclusionsApatinib could enhance the anti-tumor effect of PTX on TNBC cells through the PI3K/p65/Bcl-xl molecular pathway, and apatinib combined with PTX might be a promising option for TNBC treatment.
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